Multifunctional macromolecules have demonstrated great potential as drug delivery vectors (Nori & Kopecek (2005) Adv. Drug Deliv. Rev. 57:609-636; Patri, et al. (2002) Curr. Opin. Chem. Biol. 6:466-471). In particular, polycationic polymers have been widely explored for many biomedical applications, including gene delivery (Verma & Somia (1997) Nature 389:239-242). One of the most commonly used cationic polymers is polyethylenimine (PEI) that has been primarily used as a nonviral gene delivery vector given its capacity to protect DNA from lysosomal degradation and promote endosomal escape (Boussif, et al. (1995) Proc. Natl. Acad. Sci. USA 92:7297-7301; Gebhart & Kabanov (2001) J. Control. Release 73:401-416; Akinc, et al. (2005) J. Gene Med. 7:657-663; Urban-Klein, et al. (2005) Gene Ther. 12:461-466). Another characteristic of PEI and other polycations, such as poly(lysine) and poly(amidoamine) (PAMAM) dendrimers, is that they spontaneously interact with biological membranes (Hong, et al. (2009) Bioconjugate Chem. 20:1503-1513; Hong, et al. (2004) Bioconjugate Chem. 15:774-782). This facilitates their cellular internalization without the need for ligands for receptor-mediated endocytosis or other internalization routes. However, toxicity issues related to the strong cationic surface charge have hindered clinical translation of the polycations in drug delivery, largely due to the lack of kinetic control over non-specific electrostatic interactions with blood components and rapid clearance by the reticuloendothelial system (RES) (Oupicky, et al. (2002) J. Drug Target. 10:93-98).
As most of the currently available anti-cancer treatment agents frequently accompany severe side effects through high toxicity to normal cells and tissues, it is highly desirable to home the drug delivery system to the tissue of interest. The passive targeting strategy using nanotechnology has proven to be efficient in reducing the toxic side effects, thereby increasing the therapeutic index of anti-cancer agents (Matsumura & Maeda (1986) Cancer Res. 46:6387-6392; Yuan, et al. (1995) Cancer Res. 55:3752-3756; Peer, et al. (2007) Nat. Nanotechnol. 2:751-760). Passive targeting utilizes the enhanced permeability and retention (EPR) effect that is defined by leaky vasculature and poor lymphatic drainage around tumors, resulting in the accumulation of the nanoscale delivery system at the tumor site. In order to take advantage of the EPR effect, a nanoscale delivery system needs to be in the range of 50-200 nm, which can be achieved using well-established manufacturing techniques (Couvreur & Vauthier (2006) Pharm. Res. 23:1417-1450; Torchilin (2005) Nat. Rev. Drug Discov. 4:145-160).
Nanohybrid particles composed of a nanoparticle surrounded by a multifunctional ligand or targeting moiety have been suggested (WO 2006/095936; US 2010/0266491). Moreover, drug delivery vectors containing stealth agents are described in WO 2009/039502. Although hybrid systems that incorporate PEI into liposomes or biodegradable nanoparticles have been suggested (Ko, et al. (2009) J. Control. Release 133:230-237; Kim, et al. (2005) Int. J. Pharm. 298:255-262; Son & Kim (2010) Biomaterials 31:134-143), the kinetics and interactions with cells have not been analyzed.